Use of the neurotoxic component of a botulinum toxin for treating a spastic muscle

ABSTRACT

A method and composition for treating a patient suffering from a disease, disorder or condition and associated pain include the administration to the patient of a therapeutically effective amount of a neurotoxin selected from a group consisting of botulinum toxin types A, B, C, D, E, F and G.

CROSS-REFERENCE

This application is a continuation in part of application Ser. No.08/627,118, filed Apr. 3, 1996, now U.S. Pat. No. 6,974,578, which is acontinuation of application Ser. No. 08/173,996, filed Dec. 28, 1993,now abandoned.

FIELD OF THE INVENTION

The present invention provides novel methods for treating variousdisorders and conditions, with Botulinum toxins. Importantly, thepresent invention provides methods useful in relieving pain related tomuscle activity or contracture and therefore is of advantage in thetreatment of, for example, muscle spasm such as Temporomandibular JointDisease, low back pain, myofascial pain, pain related to spasticity anddystonia, as well as sports injuries, and pain related to contracturesin arthritis.

BACKGROUND OF THE INVENTION

Heretofore, Botulinum toxins, in particular Botulinum toxin type A, hasbeen used in the treatment of a number of neuromuscular disorders andconditions involving muscular spasm; for example, strabismus,blepharospasm, spasmodic torticollis (cervical dystonia), oromandibulardystonia and spasmodic dysphonia (laryngeal dystonia). The toxin bindsrapidly and strongly to presynaptic cholinergic nerve terminals andinhibits the exocytosis of acetylcholine by decreasing the frequency ofacetylcholine release. This results in local paralysis and hencerelaxation of the muscle afflicted by spasm.

For one example of treating neuromuscular disorders, see U.S. Pat. No.5,053,005 to Borodic, which suggests treating curvature of the juvenilespine, i.e., scoliosis, with an acetylcholine release inhibitor,preferably Botulinum toxin A.

For the treatment of strabismus with Botulinum toxin type A, see Elston,J. S., et al., British Journal of Ophthalmology, 1985, 69, 718-724 and891-896. For the treatment of blepharospasm with Botulinum toxin type A,see Adenis, J. P., et al., J. Fr. Ophthalmol., 1990, 13 (5) at pages259-264. For treating squint, see Elston, J. S., Eye, 1990, 4(4):VII.For treating spasmodic and oromandibular dystonia torticollis, seeJankovic et al., Neurology, 1987, 37, 616-623.

Spasmodic dysphonia has been treated with Botulinum toxin type A. SeeBlitzer et al., Ann. Otol. Rhino. Laryngol, 1985, 94, 591-594. Lingualdystonia was treated with Botulinum toxin type A according to Brin etal., Adv. Neurol. (1987) 50, 599-608. Finally, Cohen et al., Neurology(1987) 37 (Suppl. 1), 123-4, discloses the treatment of writer's crampwith Botulinum toxin type A.

The term botulinum toxin is a generic term embracing the family oftoxins produced by the anaerobic bacterium Clostridium botulinum and, todate, seven immunologically distinct neurotoxins have been identified.These have been given the designations A, B, C, D, E, F and G. Forfurther information concerning the properties of the various Botulinumtoxins, reference is made to the article by Jankovic and Brin, The NewEngland Journal of Medicine, No. 17, 1990, pp. 1186-1194, and to thereview by Charles L. Hatheway in Chapter 1 of the book entitledBotulinum Neurotoxin and Tetanus Toxin, L. L. Simpson, Ed., published byAcademic Press Inc. of San Diego, Calif., 1989, the disclosures in whichare incorporated herein by reference.

The neurotoxic component of a botulinum toxin has a molecular weight ofabout 150 kilodaltons and is thought to comprise a short polypeptidechain of about 50 kD which is considered to be responsible for the toxicproperties of the toxin, i.e., by interfering with the exocytosis ofacetylcholine, by decreasing the frequency of acetylcholine release, anda larger polypeptide chain of about 100 kD which is believed to benecessary to enable the toxin to bind to the presynaptic membrane.

The “short” and “long” chains are linked together by means of a simpledisulfide bridge. (It is noted that certain serotypes of botulinumtoxin, e.g., type E, may exist in the form of a single chain un-nickedprotein, as opposed to a dichain. The single chain form is less activebut may be converted to the corresponding dichain by nicking with aprotease, e.g., trypsin. Both the single and the dichain as well as theneurotoxic component are useful in the method of the present invention.)

In general, four physiologic groups of C. botulinum are recognized (I,II, III, IV). The organisms capable of producing a serologicallydistinct toxin may come from more than one physiological group. Forexample, Type B and F toxins can be produced by strains from Group I orII. In addition, other strains of clostridial species (C. baratii, typeF; C. butyricum, type E; C. novyi, type C₁ or D) have been identifiedwhich can produce botulinum neurotoxins.

Immunotoxin conjugates of ricin and antibodies, which are characterizedas having enhanced cytotoxicity through improving cell surface affinity,are disclosed in European Patent Specification 0 129 434. The inventorsnote that botulinum toxin may be utilized in place of ricin.

Botulinum toxin neurotoxin component can be obtained commercially byestablishing and growing cultures of C. botulinum in a fermenter andthen harvesting and purifying the fermented mixture and separating theneurotoxic component from the botulinum toxin complex in accordance withknown techniques. See e.g. Boroff D. A. et al., On the question ofpermeability of the blood-brain barrier to botulinum toxin, Int ArchAllergy Appl Immunol 1975; 48(4):495-504.

Botulinum toxin type A, the toxin type generally utilized in treatingneuromuscular conditions, is currently available commercially fromseveral sources; for example, from Porton Products Ltd. UK, under thetrade name “DYSPORT,” and from Allergan, Inc., Irvine, Calif., under thetrade name BOTOX®.

It is one object of the invention to provide novel treatments ofneuromuscular disorders and conditions with various Botulinum toxintypes. It is another object of the present invention to relieve painwith various botulinum toxin types.

SUMMARY OF THE INVENTION

The present invention provides a method for relieving pain, associatedwith muscle contractions, a composition and a method of treatingconditions such as cholinergic controlled secretions including excessivesweating, lacrimation and mucus secretions and a method for treatingsmooth muscle disorders including, but not limited to, spasms in thesphincter of the cardiovascular arteriole, gastrointestinal system,urinary, gall bladder and rectum, which method comprises administeringto the patient suffering from said disorder or condition atherapeutically effective amount of a botulinum toxin selected from thegroup consisting of botulinum toxin types A, B, C, D, E, F and G.

Each serotype of botulinum toxin has been identified as immunologicallydifferent proteins through the use of specific antibodies. For example,if the antibody (antitoxin) recognizes, that is, neutralizes thebiological activity of, for example, type A it will not recognize typesB, C, D, E, F or G.

While all of the botulinum toxins appear to be zinc endopeptidases, themechanism of action of different serotypes, for example, A and E withinthe neuron appear to be different than that of Type B. In addition, theneuronal surface “receptor” for the toxin appears to be different forthe serotypes.

In the area of use of the botulinum toxins in accordance with thepresent invention with regard to organ systems which involve the releaseof neurotransmitter, it is expected to introduce the toxins A, B, C, D,E, F, and G directly by local injections.

DETAILED DESCRIPTION

The botulinum toxins used according to the present invention can be aneurotoxic component of the botulinum toxins type A, B, C, D, E, F andG.

The physiologic groups of Clostridium botulinum types are listed inTable I.

TABLE I Physiol gic Groups of Clostridium botulinum Phenotypically ToxinRelated Sero- Milk Glucose Phages & Clostridium Group Type BiochemistryDigest Fermentation Lipase Plasmids (nontoxigenic) I A, B, F proteolyticsaccharolytic + + + + C. sporogenes II B, E, F nonproteolyticsaccharolytic − + + + psychotrophic III C, D nonproteolyticsaccharolytic ± + + + C. novyi IV G proteolytic nonsaccharolytic + − − −C. subterminaleThese toxin types may be produced by selection from the appropriatephysiologic group of Clostridium botulinum organisms. The organismsdesignated as Group I are usually referred to as proteolytic and produceBotulinum toxins of types A, B and F. The organisms designated as GroupII are saccharolytic and produce Botulinum toxins of types B, E and F.The organisms designated as Group III produce only Botulinum toxin typesC and D and are distinguished from organisms of Groups I and II by theproduction of significant amounts of propionic acid. Group IV organismsonly produce neurotoxin of type G. The production of any and all of theBotulinum toxin types A, B, C, D, E, F and G are described in Chapter 1of Botulinum Neurotoxin and Tetanus Toxin, cited above, and/or thereferences cited therein. Botulinum toxins types B, C, D, E, F and G arealso available from various species of clostridia.

Currently fourteen species of clostridia are considered pathogenic. Mostof the pathogenic strains produce toxins which are responsible for thevarious pathological signs and symptoms. Organisms which producebotulinum toxins have been isolated from botulism outbreaks in humans(types A, B, E and F) and animals (types C and D). Their identities weredescribed through the use of specific antitoxins (antibodies) developedagainst the earlier toxins. Type G toxin was found in soil and has lowtoxigenicity. However, it has been isolated from autopsy specimens, butthus far there has not been adequate evidence that type G botulism hasoccurred in humans.

Preferably, the toxin is administered by means of intramuscularinjection directly into a local area such as a spastic muscle,preferably in the region of the neuromuscular junction, althoughalternative types of administration (e.g., subcutaneous injection),which can deliver the toxin directly to the affected region, may beemployed where appropriate. The toxin can be presented as a sterilepyrogen-free aqueous solution or dispersion and as a sterile powder forreconstitution into a sterile solution or dispersion.

Where desired, tonicity adjusting agents such as sodium chloride,glycerol and various sugars can be added. Stabilizers such as humanserum albumin may also be included. The formulation may be preserved bymeans of a suitable pharmaceutically acceptable preservative such as aparaben, although preferably it is unpreserved.

It is preferred that the toxin is formulated in unit dosage form; forexample, it can be provided as a sterile solution in a vial or as a vialor sachet containing a lyophilized powder for reconstituting a suitablevehicle such as saline for injection.

In one embodiment, the botulinum toxin is formulated in a solutioncontaining saline and pasteurized human serum albumin, which stabilizesthe toxin and minimizes loss through non-specific adsorption. Thesolution is sterile filtered (0.2 micron filter), filled into individualvials and then vacuum-dried to give a sterile lyophilized powder. Inuse, the powder can be reconstituted by the addition of sterileunpreserved normal saline (sodium chloride 0.9% for injection).

The dose of toxin administered to the patient will depend upon theseverity of the condition; e.g. the number of muscle groups requiringtreatment, the age and size of the patient and the potency of the toxin.The potency of the toxin is expressed as a multiple of the LD₅₀ valuefor the mouse, one unit (U) of toxin being defined as being the amountof toxin which kills 50% of a group of Swiss-Webster mice, weighingbetween 17 and 22 grams each.

The dosages used in human therapeutic applications are roughlyproportional to the mass of muscle being injected. Typically, the doseadministered to the patient may be up from about 0.01 to about 1,000units; for example, up to about 500 units, and preferably in the rangefrom about 80 to about 460 units per patient per treatment, althoughsmaller of larger doses may be administered in appropriate circumstancessuch as up to about 50 units for the relief of pain and in controllingcholinergic secretions.

As the physicians become more familiar with the use of this product, thedose may be changed. In the Botulinum toxin type A, available fromPorton, DYSPORT, 1 nanogram (ng) contains 40 units. 1 ng of theBotulinum toxin type A, available from Allergan, Inc., i.e., BOTOX®,contains 4 units. The potency of Botulinum toxin and its long durationof action mean that doses will tend to be administered on an infrequentbasis. Ultimately, however, both the quantity of toxin administered andthe frequency of its administration will be at the discretion of thephysician responsible for the treatment and will be commensurate withquestions of safety and the effects produced by the toxin.

In some circumstances, particularly in the relief of pain associatedwith sports injuries, such as, for example, charleyhorse, botulinum typeF, having a short duration activity, is preferred.

The invention will now be illustrated by reference to the followingnonlimiting examples.

In each of the examples, appropriate areas of each patient can beinjected with a sterile solution containing the confirmation of aneurotoxic component of a botulinum toxin free of, or substantially freeof, the botulinum toxin complex proteins. “Substantially free” meansthat there is present with the neurotoxic component less than 20% (i.e.10%-20%) and preferably less than 10% (i.e. 1%-9.9%) of the botulinumtoxin complex proteins. The botulinum toxin complex proteins (in thecase of a 900 kDa botulinum toxin type A complex) can comprise about 750kDa of several different proteins which accompany the 150 kDa botulinumtoxin protein (the neurotoxic component). Thus, the botulinum toxincomplex proteins (which excludes the 150 kDa botulinum toxin molecule,which is the neurotoxic component) can comprise as many as fivehaemagglutinin proteins (with a total molecular weight of about 600 kDa)and a non-toxic non-haemaggtutinin (NTNH) component with a molecularweight of about 150 kDa. The (nontoxic) botulinum toxin complex proteinsare generally thought to protect the botulinum toxin molecule (theneurotoxic component) from digestive enzymes during its passage throughthe gastro-intestinal tract. Total patient doses range from about 0.01units to 460 units. Before injecting any muscle group, carefulconsideration is given to the anatomy of the muscle group, the aim beingto inject the area with the highest concentration of neuromuscularjunctions, if known. Before injecting the muscle, the position of theneedle in the muscle is confirmed by putting the muscle through itsrange of motion and observing the resultant motion of the needle end.General anaesthesia, local anaesthesia and sedation are used accordingto the age of the patient, the number of sites to be injected, and theparticular needs of the patient. More than one injection and/or sites ofinjection may be necessary to achieve the desired result. Also, someinjections, depending on the muscle to be injected, may require the useof fine, hollow, teflon-coated needles, guided by electromyography.

Following injection, it is noted that there are no systemic or localside effects and none of the patients are found to develop extensivelocal hypotonicity. The majority of patients show an improvement infunction both subjectively and when measured objectively.

Example 1 The Use of Botulinum Toxin Type in the Treatment of TardiveDyskinesia

A male patient, age 45, suffering from tardive dyskinesia resulting fromthe treatment with an antipsychotic drug, such as Thorazine or Haldol,is treated with 150 units of the neurotoxic component of a botulinumtoxin type A free of or substantially free of the botulinum toxincomplex proteins, by direct injection of such toxin into the facialmuscles. After 1-3 days, the symptoms of tardive dyskinesia, i.e.,orofacial dyskinesia, athetosis, dystonia, chorea, tics and facialgrimacing, etc. are markedly reduced.

Example 1(a)

The method of Example 1 is repeated, except that a patient sufferingfrom tardive dyskinesia is injected with 50-200 units of the neurotoxiccomponent of a botulinum toxin type B free of or substantially free ofthe botulinum toxin complex proteins. A similar result is obtained.

Example 1(b)

The method of Example 1 is repeated, except that a patient sufferingfrom tardive dyskinesia is injected with 50-200 units of the neurotoxiccomponent of a botulinum toxin type C free of or substantially free ofthe botulinum toxin complex proteins. A similar result is obtained.

Example 1(c)

The method of Example 1 is repeated, except that a patient sufferingfrom tardive dyskinesia is injected with 50-200 units of the neurotoxiccomponent of a botulinum toxin type D free of or substantially free ofthe botulinum toxin complex proteins. A similar result is obtained.

Example 1(d)

The method of Example 1 is repeated, except that a patient sufferingfrom tardive dyskinesia is injected with 50-200 units of the neurotoxiccomponent of a botulinum toxin type E free of or substantially free ofthe botulinum toxin complex proteins. A similar result is obtained.

Example 1(e)

The method of Example 1 is repeated, except that a patient sufferingfrom tardive dyskinesia is injected with 50-200 units of the neurotoxiccomponent of a botulinum toxin type F free of or substantially free ofthe botulinum toxin complex proteins. A similar result is obtained.

Example 1(f)

The method of Example 1 is repeated, except that a patient sufferingfrom tardive dyskinesia is injected with 50-200 units of the neurotoxiccomponent of a botulinum toxin type G free of or substantially free ofthe botulinum toxin complex proteins. A similar result is obtained.

Example 2 The Use of Botulinum Toxin Type A in the Treatment ofSpasmodic Torticollis

A male, age 45, suffering from spasmodic torticollis, as manifested byspasmodic or tonic contractions of the neck musculature, producingstereotyped abnormal deviations of the head, the chin being rotated toone side, and the shoulder being elevated toward the side at which thehead is rotated, is treated by injection with 100-1,000 units of theneurotoxic component of botulinum toxin type A free of or substantiallyfree of the botulinum toxin complex proteins. After 3-7 days, thesymptoms are substantially alleviated; i.e., the patient is able to holdhis head and shoulder in a normal position.

Example 2(a)

The method of Example 2 is repeated, except that a patient sufferingfrom spasmodic torticollis is injected with 100-1,000 units of theneurotoxic component of botulinum toxin type B free of or substantiallyfree of the botulinum toxin complex proteins. A similar result isobtained.

Example 2(b)

The method of Example 2 is repeated, except that a patient sufferingfrom spasmodic torticollis is injected with 100-1,000 units of theneurotoxic component of botulinum toxin type C free of or substantiallyfree of the botulinum toxin complex proteins. A similar result isobtained.

Example 2(c)

The method of Example 2 is repeated, except that a patient sufferingfrom spasmodic torticollis is injected with 100-1,000 units of theneurotoxic component of botulinum toxin type D free of or substantiallyfree of the botulinum toxin complex proteins. A similar result isobtained.

Example 2(d)

The method of Example 2 is repeated, except that a patient sufferingfrom spasmodic torticollis is injected with 100-1,000 units of theneurotoxic component of botulinum toxin type E free of or substantiallyfree of the botulinum toxin complex proteins. A similar result isobtained.

Example 2(e)

The method of Example 2 is repeated, except that a patient sufferingfrom spasmodic torticollis is injected with 100-1,000 units of theneurotoxic component of botulinum toxin type F free of or substantiallyfree of the botulinum toxin complex proteins. A similar result isobtained.

Example 2(f)

The method of Example 2 is repeated, except that a patient sufferingfrom spasmodic torticollis is injected with 100-1,000 units of theneurotoxic component of botulinum toxin type G free of or substantiallyfree of the botulinum toxin complex proteins. A similar result isobtained.

Example 3 The Use of Botulinum Toxin in the Treatment of EssentialTremor

A male, age 45, suffering from essential tremor, which is manifested asa rhythmical oscillation of head or hand muscles and is provoked bymaintenance of posture or movement, is treated by injection with50-1,000 units of the neurotoxic component of botulinum toxin type Afree of or substantially free of the botulinum toxin complex proteins.After two to eight weeks, the symptoms are substantially alleviated;i.e., the patient's head or hand ceases to oscillate.

Example 3(a)

The method of Example 3 is repeated, except that a patient sufferingfrom essential tremor is injected with 100-1,000 units of the neurotoxiccomponent of botulinum toxin type B free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 3(b)

The method of Example 3 is repeated, except that a patient sufferingfrom essential tremor is injected with 100-1,000 units of the neurotoxiccomponent of botulinum toxin type C free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 3(c)

The method of Example 3 is repeated, except that a patient sufferingfrom essential tremor is injected with 100-1,000 units of the neurotoxiccomponent of botulinum toxin type D free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 3(d)

The method of Example 3 is repeated, except that a patient sufferingfrom essential tremor is injected with 100-1,000 units of the neurotoxiccomponent of botulinum toxin type E free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 3(e)

The method of Example 3 is repeated, except that a patient sufferingfrom essential tremor is injected with 100-1,000 units of the neurotoxiccomponent of botulinum toxin type F free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 3(f)

The method of Example 3 is repeated, except that a patient sufferingfrom essential tremor is injected with 100-1,000 units of the neurotoxiccomponent of botulinum toxin type G free of or substantially free of thebotulinum toxin complex. A similar result is obtained.

Example 4 The Use of Botulinum Toxin in the Treatment of SpasmodicDysphonia

A male, age 45, unable to speak clearly, due to spasm of the vocalchords, is treated by injection of the vocal chords with 80-500 units ofthe neurotoxic component of botulinum toxin type A free of orsubstantially free of the botulinum toxin complex proteins. After 3-7days, the patient is able to speak clearly.

Example 4(a)

The method of Example 4 is repeated, except that a patient sufferingfrom spasmodic dysphonia is injected with 80-500 units of the neurotoxiccomponent of botulinum toxin type B free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 4(b)

The method of Example 4 is repeated, except that a patient sufferingfrom spasmodic dysphonia is injected with 80-500 units of the neurotoxiccomponent of botulinum toxin type C free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 4(c)

The method of Example 4 is repeated, except that a patient sufferingfrom spasmodic dysphonia is injected with 80-500 units of the neurotoxiccomponent of botulinum toxin type D free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 4(d)

The method of Example 4 is repeated, except that a patient sufferingfrom spasmodic dysphonia is injected with 80-500 units of the neurotoxiccomponent of botulinum toxin type E free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 4(e)

The method of Example 4 is repeated, except that a patient sufferingfrom spasmodic dysphonia is injected with 80-500 units of the neurotoxiccomponent of botulinum toxin type F free of or substantially free of thebotulinum toxin complex proteins. A similar result is obtained.

Example 4(f)

The method of Example 4 is repeated, except that a patient sufferingfrom spasmodic dysphonia is injected with 80-500 units of the neurotoxiccomponent of botulinum toxin type G free of or substantially free of thebotulinum toxin proteins. A similar result is obtained.

Example 5 The Use of Botulinum Toxin Types A-G in the Treatment ofExcessive Sweating, Lacrimation or Mucus Secretion or Other CholinergicControlled Secretions

A male, age 65, with excessive unilateral sweating is treated byadministering 0.01 to 50 units, depending upon degree of desired effect,of the neurotoxic component of a botulinum toxin free of orsubstantially free of the botulinum toxin complex proteins. The largerthe dose, usually the greater spread and duration of effect. Small dosesare used initially. Any serotype toxin alone or in combination could beused in this indication. The administration is to the gland nerveplexus, ganglion, spinal cord or central nervous system to be determinedby the physician's knowledge of the anatomy and physiology of the targetglands and secretary cells. In addition, the appropriate spinal cordlevel or brain area can be injected with the toxin (although this wouldcause many effects, including general weakness). Thus, the gland (ifaccessible) or the nerve plexus or ganglion are the targets of choice.Excessive sweating, tearing (lacrimation), mucus secretion orgastrointestinal secretions are positively influenced by the cholinergicnervous system. Sweating and tearing are under greater cholinergiccontrol than mucus or gastric secretion and would respond better totoxin treatment. However, mucus and gastric secretions could bemodulated through the cholinergic system. All symptoms would be reducedor eliminated with toxin therapy in about 1-7 days. Duration would beweeks to several months.

Example 6 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms in Smooth Muscle Disorders Such as Sphincters of theCardiovascular Arteriole, Gastrointestinal System, Urinary or GallBladder, Rectal, Etc.

A male, age 30-40, with a constricted pyloric valve which prevents hisstomach from emptying, is treated by administering 1-50 units of theneurotoxic component of a botulinum toxin free of or substantially freeof the botulinum toxin complex proteins. The administration is to thepyloric valve (which controls release of stomach contents into theintestine) divided into 2 to 4 quadrants, injections made with anyendoscopic device or during surgery. In about 1-7 days, normal emptyingof the stomach, elimination or drastic reduction in regurgitationoccurs.

Example 7 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inTemporal Mandibular Joint Disorders

A female, age 35, is treated by administration of 0.1 to 50 units totalof the neurotoxic component of a botulinum toxin free of orsubstantially free of the botulinum toxin complex proteins. Theadministration is to the muscles controlling the closure of the jaw.Overactive muscles may be identified with EMG (electromyography)guidance. Relief of pain associated with muscle spasms, possiblereduction in jaw clenching occurs in about 1-3 days.

Example 8 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inConditions Secondary to Sports Injuries (Charleyhorse)

A male, age 20, with severe cramping in thigh after sports injury istreated by administration of a short duration toxin, possible low dose(0.1-25 units) of preferably type F to the muscle and neighboringmuscles which are in contraction (“cramped”). Relief of pain occurs in1-7 days. The neurotoxic component of the botulinum toxin isadministered free of or substantially free of the botulinum toxincomplex proteins.

Example 9 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inSmooth Muscle Disorders Such as Gastrointestinal Muscles

A female, age 35, with spastic colitis, is treated with 1-100 units ofthe neurotoxic component of a botulinum toxin free of or substantiallyfree of the botulinum toxin complex proteins, the dosage being dividedinto several areas, enema (1-5 units) delivered in the standard enemavolume, titrate dose, starting with the lowest dose. Injection is to therectum or lower colon or a low dose enema may be employed. Cramps andpain associated with spastic colon are relieved in 1-10 days.

Example 10 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inSpasticity Conditions Secondary to Stroke, Traumatic Brain or SpinalCord Injury

A male, age 70, post-stroke or cerebral vascular event, is injected with50 to 300 units of the neurotoxic component of a botulinum toxin free ofor substantially free of the botulinum toxin complex proteins,administered in the major muscles involved in severe closing of hand andcurling of wrist and forearm or the muscles involved in the closing ofthe legs such that the patient and attendant have difficulty withhygiene. Relief of these symptoms occurs in 7 to 21 days.

Example 11 The Use of Botulinum Toxin Types A-G in the Treatment ofPatients with Swallowing Disorders

A patient with a swallowing disorder caused by excessive throat musclespasms is injected with about 1 to about 300 units of the neurotoxiccomponent of a botulinum toxin free of or substantially free of thebotulinum toxin complex proteins, administered in the throat muscles.Relief the swallowing disorder occurs in about 7 to about 21 days.

Example 12 The Use of Botulinum Toxin Types A-G in the Treatment ofPatients with Tension Headache

A patient with a tension headache caused by excessive throat musclespasms is injected with about 1 to about 300 units of the neurotoxiccomponent of a botulinum toxin free of or substantially free of thebotulinum toxin complex proteins, administered in muscles of the headand upper neck. Relief the tension headache occurs in about 1 to about 7days.

Example 13 The Use of a Neurotoxic Component of a Botulinum Toxin TypesA-G in the Treatment of Patients with Strabismus

A patient with strabismus can be treated by injecting between about 1 toabout 5 units of the neurotoxic component of a botulinum toxin type Afree of or substantially free of the botulinum toxin complex proteins(or between about 50 to about 250 units of the neurotoxic component of abotulinum toxin type B, free of or substantially free of the botulinumtoxin complex proteins) into extraocular muscles (i.e. into the right orleft medial rectus muscles), the amount injected varying based upon boththe size of the muscle to be injected and the extent of muscle paralysisdesired (i.e. amount of diopter correction desired).

Alleviation of the strabismus occurs in about 1 to about 7 days.

Example 14 The Use of a Neurotoxic Component of a Botulinum Toxin TypesA-G in the Treatment of Patients with Blepharospasm

A patient with blepharospasm can be treated by injecting between about 1to about 5 units of the neurotoxic component of a botulinum toxin type Afree of or substantially free of the botulinum toxin complex proteins(or between about 50 to about 250 units of the neurotoxic component of abotulinum toxin type B, free of or substantially free of the botulinumtoxin complex proteins) into the lateral pre-tarsal orbicularis oculimuscle of the upper lid and the lateral pre-tarsal orbicularis oculi ofthe lower lid., the amount injected varying based upon both the size ofthe muscle to be injected and the extent of muscle paralysis desired

Alleviation of the blepharospasm occurs in about 1 to about 7 days.

Although there has been hereinabove described a use of botulinum toxinsfor treating various disorders, conditions and pain, in accordance withthe present invention, for the purpose of illustrating the manner inwhich the invention may be used to advantage, it should be appreciatedthat the invention is not limited thereto since many obviousmodifications can be made, and it is intended to include within thisinvention any such modifications as will fall within the scope of theappended claims. Accordingly, any and all modifications, variations, orequivalent arrangements which may occur to those skilled in the art,should be considered to be within the scope of the present invention asdefined in the appended claims.

1. A method for treating strabismus, wherein said method is a humanmedical application and comprises the step of administering to a humanpatient a therapeutically effective amount of a neurotoxic component ofa botulinum toxin type B to thereby treat strabismus wherein theneurotoxic component administered to the human patient has a molecularweight of about 150 kilodaltons, wherein the neurotoxic component isadministered by intramuscular injection or by subcutaneous injection,and wherein the administration of the neurotoxic component results inalleviation of the strabismus within 1 day to 7 days.
 2. The method ofclaim 1, wherein between about 0.01 units and about 500 units of theneurotoxic component is administered.
 3. The method of claim 1, whereinbetween about 80 units and about 460 units of the neurotoxic componentis administered.
 4. A method for treating strabismus, the methodcomprising the step of administering to a human patient atherapeutically effective amount of a neurotoxic component of botulinumtoxin type B to treat strabismus, wherein the neurotoxic component isadministered by intramuscular injection or by subcutaneous injection,and the administration of the neurotoxic component results inalleviation of the strabismus within 1 day to 7 days.
 5. The method ofclaim 4, wherein between about 0.01 units and about 500 units of theneurotoxic component is administered.
 6. The method of claim 4, whereinbetween about 80 units and about 460 units of the neurotoxic componentis administered.